Should children with severe cognitive impairment receive solid organ transplants?
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Child↗
Biomedical subjects
S Ashwal
Publications and source records attributed to S Ashwal.
Life expectancy and median survival time in the permanent vegetative state.
The authors studied life expectancy and risk factors for mortality of persons in the vegetative state (VS). The study participants were 1,021 California patients in the VS during 1981-1996. Because of the large sample size, the authors were able to use multivariate methods to assess the effect of several risk factors on mortality. The authors found a strong secular trend in infant mortality, with rates in the mid-1990s being only one third of those in the early 1980s (P < 0.01). A smaller secular trend was observed for children aged 2-10 years and none for older patients. The mortality risk for older patients fell by approximately 8% for each year since the onset of the VS. The need for gastrostomy feeding was associated with a substantially higher risk, especially for infants and older patients (P < 0.01). Ventilator dependence also appeared to be a risk factor. On the basis of recent mortality rates, life expectancy in the VS is frequently higher than has generally been thought. For example, it is 10.5 additional years (+/- 2 years) for a 15-year-old patient who has been in the VS for 1 year, and 12.2 years for a 15-year-old patient who has been in the VS for 4 years.
Adolescent↗
Proton magnetic resonance spectroscopy: clinical applications in children with nervous system diseases.
With the use of software modifications of existing magnetic resonance imaging technology, proton magnetic resonance spectroscopy yields insight noninvasively regarding brain biochemistry. Biochemical information can be obtained directly both regionally and longitudinally. This article summarizes the technological basis for magnetic resonance spectroscopy as well as its established applications to disorders of interest to the pediatric neurologist. Future directions for magnetic resonance spectroscopy study and advances to be expected in the near future are also highlighted.
Adolescent↗
Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion in the rat pup.
Our studies examined the hypothesis that the distribution of cerebral injury after a focal ischemic insult in the immature rat pup is associated with the regional distribution of nitric oxide synthase (NOS) activity and that differences in the vulnerability to ischemia between pup and adult might be related to differences in cofactor availability. We measured NOS activity in well-defined regions prone to become either core or penumbra in controls and at different times (end of occlusion, 0.5 h, and 24 h reperfusion) after middle cerebral artery occlusion (MCAO) from the right and left hemispheres in a 14- to 18-day-old rat pup filament model. Three groups of corresponding isoflurane sham controls were also included. "Core" NOS activity for combined right and left hemispheres ranged from 113% to 217% more than "penumbral" regions in control and sham groups. In the three MCAO groups, marked decreases in ischemic core and penumbral NOS activity were seen; however, core NOS remained higher than penumbral regions bilaterally. The effects of cofactor addition (10 microM tetrahydrobiopterin, 3 microM flavin adenine dinucleotide, and 3 microM flavin mononucleotide) on NOS activity were similar in "core" and "penumbral" regions in control and sham groups. However, after 24 h MCAO, cofactor addition preferentially increased NOS activity in the ischemic hemisphere. Co-factor addition in the pup also had a greater effect on enhancing NOS activity in all regions compared with the adult. Greater NOS activity in core regions in the rat pup, as in the adult, could in part, explain the increased vulnerability of that region to ischemia. NOS activity also can be influenced by the availability of cofactors and this effect may be greater in the immature animal.
Animals↗
Proton magnetic resonance spectroscopy: an emerging technology in pediatric neurology research.
Proton magnetic resonance spectroscopy (MRS) is an emerging technology that allows for the quantitative noninvasive assessment of regional brain biochemistry. The capacity to carry out MRS studies requires existing magnetic resonance imaging (MRI) technology platforms and the purchase of commercially available software modifications. In this review, the physical basis for MRS will be presented leading to an understanding of its potential applications and limitations within the clinical research milieu. Thus far, within pediatric neurology, proton MRS studies have been used to assist in the prediction of outcome in a variety of settings of acquired brain injuries (perinatal asphyxia, near drowning). In addition, proton MRS has been used to document disturbances in oxidative metabolism in neurometabolic disorders, assisting in defining phenotype and the response to therapeutic interventions. In epilepsy, spectroscopic studies have been useful in localizing the epileptogenic zone in intractable focal epilepsies. Future applications of proton MRS will also be highlighted. These include its use as a means of observing the transport and metabolism of various compounds in the brain, its concurrent application with other nuclear magnetic resonance techniques such as MRI and functional MRI, and finally its potential as a means of assessing the short-term effects of any CNS targeted pharmacologic interventions.
Brain↗
Core and penumbral nitric oxide synthase activity during cerebral ischemia and reperfusion.
BACKGROUND AND PURPOSE: The present studies examined the hypothesis that the distribution of cerebral injury after a focal ischemic insult is associated with the regional distribution of nitric oxide synthase (NOS) activity. METHODS: Based on previous studies that certain anatomically well-defined areas are prone to become either core or penumbra after middle cerebral artery occlusion (MCAO), we measured NOS activity in these areas from the right and left hemispheres in a spontaneously hypertensive rat filament model. Four groups were studied: (1) controls (immediate decapitation); (2) 1.5 hours of MCAO with no reperfusion (R0); (3) 1.5 hours of MCAO with 0.5 hour of reperfusion (R0.5); and (4) 1.5 hours of MCAO with 24 hours of reperfusion (R24). Three groups of corresponding isoflurane sham controls were also included: 1.5 (S1.5) or 2 (S2.0) hours of anesthesia and 1.5 hours of anesthesia+24 hours of observation (S24). RESULTS: Control core NOS activity for combined right and left hemispheres was 129% greater than penumbral NOS activity (P<0.05). Combined core NOS activity was also greater (P<0.05) in the three sham groups: 208%, 122%, and 161%, respectively. In the three MCAO groups, ischemic and nonischemic core NOS remained higher than penumbral regions (P<0.05). However, NOS activity was lower in the ischemic than in the nonischemic core in all three groups: R0 (29% lower), R0.5 (48%), and R24 (86%) (P<0.05). Addition of cofactors (10 micromol/L tetrahydrobiopterin, 3 micromol/L flavin adenine dinucleotide, and 3 micromol/L flavin mononucleotide) increased NOS activity in all groups and lessened the decrease in ischemic core and penumbral NOS. CONCLUSIONS: Greater NOS activity in core regions could explain in part the increased vulnerability of that region to ischemia and could theoretically contribute to the progression of the infarct over time. The data also suggest that NOS activity during ischemia and reperfusion could be influenced by the availability of cofactors.
Anesthetics, Inhalation↗
1H-magnetic resonance spectroscopy-determined cerebral lactate and poor neurological outcomes in children with central nervous system disease.
By using proton magnetic resonance spectroscopy ((1)H-MRS), cerebral lactate has been shown to be elevated in a wide variety of pediatric and adult neurological diseases. In this study we compared 36 newborns, infants, and children with elevated lactate peaks on (1)H-MRS with 61 patients without an identifiable lactate signal. (1)H-MRS was acquired from the occipital gray and parietal white matter (8 cm3 volume, STEAM sequence with echo time = 20 msec, repetition time = 3.0 seconds) and data were expressed as ratios of different metabolite peak areas (N-acetylaspartate [NA]/creatine [Cr], NA/choline [Ch], and Ch/Cr) and the presence of a characteristic lactate doublet peak at 1.3 ppm. Outcomes (Pediatric Cerebral Performance Category Scale score; PCPCS) were assigned 6 to 12 months after injury. Patients with lactate peaks were more likely to have suffered a cardiac arrest, were more often hyperglycemic, and had lower Glasgow Coma Scale scores on admission. They were also more likely to have abnormal metabolite ratios when compared with age-matched controls or with patients without detectable lactate. Of prognostic importance, patients with increased lactate were more likely to be severely disabled (39% vs 10%), survive in a persistent vegetative state (13% vs 2%), or have died (39% vs 7%). In contrast, patients with similar conditions without increased lactate were more likely to have had a good outcome (23% vs 3%) or recovered to a mild (38% vs 6%) or moderate disability (20% vs 0%). Our data suggest that (1)H-MRS is useful in the prediction of long-term outcomes in children with neurological disorders. Patients with elevated cerebral lactate are more likely to die acutely or are at greater risk for serious long-term disability.
Brain Diseases↗
Prognostic value of 1H-MRS in perinatal CNS insults.
The authors studied 37 term neonates (38-42 gestational weeks) at 1-11 days after central nervous system insult to determine whether proton magnetic resonance spectroscopy (1H-MRS) of the occipital gray/parietal white matter was useful in predicting outcomes. Etiologies included asphyxia, 18; sepsis/meningitis, 8; metabolic disorders, 5; stroke, 4; and trauma, 2. 1H-MRS data (1.5T; 8 cm3 vol, stimulated echo acquisition mode sequence, TE = 20 ms, TR = 3000 ms) were expressed as metabolite peak area ratios (NAA/Cr, NAA/Cho, Cho/Cr) and the presence or absence of lactate. Outcomes were assessed at 6 to 12 months post-insult using the Pediatric Cerebral Performance Scale and were dichotomized as follows: good/moderate outcome (good, mild or moderate disability) or poor outcome (severe disability, persistent vegetative state, death). Neonates with poor outcomes had significantly lower NAA/Cho and significantly higher Cho/Cr ratios in the occipital region, as compared with patients with good/moderate outcomes. No neonates with good/moderate outcomes had metabolite ratios that exceeded 2 standard deviations from the mean. In addition, the absence of lactate on 1H-MRS correlated with a good/moderate outcome. The study also showed that 1H-MRS metabolite ratio data, added to either the Sarnat or EEG scores, enhanced the correlation between these prognostic factors and outcomes. 1H-MRS provides additional objective data early after a wide variety of perinatal neurologic insults to enhance outcome prediction.
Apgar Score↗
Long-term ventilation in children with severe central nervous system impairment.
Absent from the list of indications for long-term ventilation (LTV) is its use for children with severe central nervous system impairment, including those with severe mental retardation or in a permanent vegetative state. Over a two year period, we evaluated eight children with severe CNS dysfunction for whom long-term ventilation was being contemplated. Of these eight patients, three were in a permanent vegetative state and the remainder were severely neurologically impaired, with minimal cognition. The following recommendations were developed: (1) LTV for patients in a permanent vegetative state is inappropriate. (2) In a patient with severe neurologic disease, the process of informed consent must be viewed as dynamic; once the patient's condition is diagnosed, discussion should begin about the likely course of the disease (upper airway obstruction, respiratory failure, or both) and available treatment options. (3) Continued efforts must be made to resolve conflicts between healthcare professionals and surrogates concerning aggressive support of children with severe CNS dysfunction. Discussions should continue even after a decision to provide long-term ventilation is made. (4) Currently, requests by surrogates for LTV in patients with severe neurologic impairment are usually honored because of respect for family values. (5) Physicians and other healthcare professionals should develop an open and fair process for determining inappropriate care. (6) Once LTV is initiated, efforts to transfer the child to home or a long-term care facility should be made. Further life-saving support should be discouraged. (7) Irremediable patient suffering is reason to refuse a surrogate request for LTV. A patient's preservable existence might be so torturous, painful, or filled with suffering that continued medical intervention would be inhumane or abusive.
Adolescent↗
Anencephaly: where do we now stand?
In 1995 the American Medical Association's ethics council issued an opinion calling for the direct procurement of organs from anencephalic newborns, making them an exception to the "dead donor" rule. Such a firestorm erupted that the Council for Ethical and Judicial Affairs withdrew its opinion. Although the AMA has called for further research into possible "consciousness" in anencephalic newborns, present studies convincingly demonstrate that the brain stems of these infants are almost completely devoid of any evidence of even primitive functional organization. New studies indicate that cerebral absence causes unusual behaviors such as stiffening and hyperirritability that can be detected prenatally. Although widespread testing and screening in recent years has drastically reduced the number of anencephalic newborns, the discussion of use continues, raising ethical issues that pertain to other marginal patients such as those in persistent vegetative states. There are two schools of thought on the permissibility of using anencephalic newborns as organ sources: physicalism and personalism. Physicalism holds that all humans are so precious that no exceptions can be made regarding organ procurement, even in the case of anencephaly. Personalism sees moral worth related to one's potential or actual mental capacities, and because of anencephalic newborns' uniqueness, believes considerable liberties can be taken here. Most bioethicists are themselves in the personalist camp, but many have questions about changing the law to allow for a proposal such as the AMA Council's, because of the social impact of that change.
Anencephaly↗
Proton MR spectroscopy after acute central nervous system injury: outcome prediction in neonates, infants, and children.
PURPOSE: To evaluate the usefulness of proton magnetic resonance (MR) spectroscopy in predicting 6-12-month neurologic outcome in children after central nervous system injuries. MATERIALS AND METHODS: Localized single-voxel, 20-msec-echo-time MR spectra (including N-acetylaspartate [NAA], choline [Ch], creatine and phosphocreatine [Cr]) were obtained in the occipital gray matter in 82 patients and 24 control patients. Patient age groups were defined as neonates (< or = 1 month [n = 23]), infants (1-18 months [n = 31]), and children (> or = 18 months [n = 28]). Metabolite ratios and the presence of lactate were determined. Linear discriminant analysis-with admission clinical data, proton MR spectroscopy findings, and MR imaging score (three-point scale based on severity of structural neuroimaging changes)-was performed to help predict outcome in each patient. Findings were then compared with the actual 6-12-month outcome assigned by a pediatric neurologist. RESULTS: Outcome on the basis of proton MR spectroscopy findings combined with clinical data and MR imaging score was predicted correctly in 91% of neonates and in 100% of infants and children. Outcome on the basis of clinical data and MR imaging score alone was 83% in neonates, 84% in infants, and 93% in children. The presence of lactate was significantly higher in patients with poor outcome than in patients with good-moderate outcomes in all three age groups (neonates, 38% vs 5%; infants, 87% vs 5%; children, 64% vs 10% [chi 2 test, P < .02]). In children with poor outcomes, NAA/Cr ratios were significantly lower in infants (P = .006) and children (P < .001), and NAA/Ch ratios were significantly lower in infants (P = .001) and neonates (P = .05). CONCLUSION: Findings at proton MR spectroscopy helped predict long-term neurologic outcomes in children after central nervous system injury.
Adolescent↗
Maturation alters cerebral NOS kinetics in the spontaneously hypertensive rat.
Using 14C-labeled arginine to 14C-labeled citrulline conversion assays in brain homogenates from 14- to 18-day-old and adult spontaneously hypertensive rats, we tested the hypotheses that maturation increases neuronal nitric oxide synthase (nNOS) activity and that this increase involves changes in cofactor availability and/or nNOS kinetics. nNOS activity (in pmol x mg(-1) x min(-1)) was 46% higher in adults (19 +/- 2) than in pups (13 +/- 1). The addition of 264 microM calmodulin (CaM), 3 microM FAD, 3 microM flavin adenine mononucleotide (FMN), and 10 microM tetrahydrobiopterin (BH4) increased NOS activity by 3, 46, 45, and 88% in pups and by 19, 40, 36, and 102% in adults, respectively. All cofactor effects were significant except for CaM in the pup homogenates. Cofactor effects were not significantly different between pup and adult homogenates, except for BH4, which increased absolute NOS activity more in adults than in pups. Values of maximal enzyme velocity (Vmax) for nNOS in the absence of added cofactors were greater in adults than in pups (104 +/- 5 vs. 53 +/- 3, P < 0.05). Addition of 3 microM FAD or 3 microM FMN increased pup Vmax values to 68 +/- 2 and 99 +/- 5, respectively, but had no effect in adults. BH4 did not affect Vmax in either group. Control values of the Michaelis-Menten constant (Km) for L-arginine were greater (P < 0.05) in pups (5.7 +/- 0.4 microM) than in adults (4.3 +/- 0.2 microM) and were significantly reduced by 10 microM BH4 to 3.8 +/- 0.2 and 2.9 +/- 0.1 microM, respectively. Neither FAD nor FMN affected Km values in either group. The results indicate that endogenous nNOS cofactor levels are not saturating in either pups or adults, changes in cofactor levels differentially affect NOS kinetics in pups and adults, and age-related differences in NOS activity result from fundamental differences in NOS kinetics. These findings support the general hypothesis that the increased vulnerability to ischemic stroke associated with maturation is due in part to corresponding increases in the capacity for nitric oxide synthesis.
Aging↗
Intravenous immunoglobulin as therapy for pediatric Guillain-Barré syndrome.
Seven children with Guillain-Barré syndrome were treated with intravenous immunoglobulin. Median patient age was 5.8 years. A standard dosage of 0.4 g/kg/day for 5 days was administered. Clinical improvement occurred on average within 2.4 +/- 1.3 days of beginning intravenous immunoglobulin. One child required mechanical ventilation for 7 days. Eight comparable children with Guillain-Barré syndrome at our institution in a prior study treated with plasmapheresis alone had similar clinical results. However, the need for admission to the pediatric intensive care unit and duration of pediatric intensive care unit stay were lower in the intravenous immunoglobulin treated group (P < .05). There were no complications with intravenous immunoglobulin therapy except for a brief episode of hypotension in one patient. Review of the literature identified 74 additional children with Guillain-Barré syndrome successfully receiving intravenous immunoglobulin therapy. We suggest intravenous immunoglobulin as initial therapy for pediatric Guillain-Barré syndrome, because it appears equally as effective as plasmapheresis and is associated with fewer complications.
Chi-Square Distribution↗
Tubefeeding and mortality in children with severe disabilities and mental retardation.
OBJECTIVE: To study the contribution of tubefeeding to mortality for children with severe disabilities and mental retardation. Previous research has suggested an association between tubefeeding and mortality. However, risk has never been determined using population-based data or defined in regard to patient variables. METHODS: Retrospective analysis of a comprehensive statewide data set comprised of 4921 children with severe disabilities and mental retardation living in community and congregate care settings. The outcome measure was mortality; primary study variables included the presence of a feeding tube, measures of functional independence, type of residence, and medical comorbidity. RESULTS: There were four findings. First, the use of a feeding tube was associated with virtually every disability. Second, when no study variables were controlled, statistically significant differences in mortality rates were noted between children who were tubefed and those who were not. The relative risk of mortality associated with use of a feeding tube was 2.1. Third, the use of a feeding tube was associated with a reduction in relative risk of mortality in children with tracheostomy (relative risk of mortality: .55). However, this association did not achieve statistical significance. Fourth, when study variables were controlled in a multivariate analysis, feeding tube use was associated with no identifiable increase in mortality among children with very severe disabilities, but was associated with an approximated doubled mortality rate among those with less severe disabilities. CONCLUSIONS: We hypothesize that the increased mortality associated with tubefeeding may be attributable to a differential increase in pulmonary disease secondary to overly vigorous nutritional maintenance and subsequent aspiration after tube placement. For children with tracheostomy this risk may be reduced. If tracheostomy proves to be associated with a relatively more favorable outcome for tubefeeding, we hypothesize that it would reflect the benefits of tracheostomy in allowing access to the airway for suctioning and ventilation. Given the observed higher mortality rates among the less severely disabled children who are tubefed and the substantial costs associated with tubefeeding, a prospective, controlled study may be clinically indicated, ethically justifiable, and economically warranted.
Adolescent↗
Brain death in the newborn. Current perspectives.
Brain death can be diagnosed in the full-term newborn, even when less than 7 days of age. An observation period of 48 hours is recommended to confirm the diagnosis. If an EEG is isoelectric or if a CBF study shows no flow, the observation period can be shortened to 24 hours. Although there are few cases of preterm infants who are brain dead, it is likely that the same time frame would be applicable. Based on available data, the risk of misdiagnosis appears exceedingly low. There have been few instances of neonates or older infants who showed minimal transient clinical or EEG recovery but with no meaningful neurologic function and all died within brief periods of time.
Blood Flow Velocity↗
Prognosis for survival and improvement in function in children with severe developmental disabilities.
OBJECTIVE: To derive prognostic data for survival and clinical improvement in children with severe developmental disabilities. STUDY DESIGN: A 13-year follow-up study of several cohorts of children initially evaluated before their first birthday. The outcomes studied were survival and improvement in condition. Methods were used to overcome limitations in previously published work on the same California data base. Of the 11,912 children who received services from the California Department of Developmental Services between January 1980 and December 1993, we focused on three cohorts defined according to mobility and need for tube feeding. RESULTS: Children who were tube fed and unable to lift their heads by ages 3 to 12 months were at high risk for early death, with a median remaining life expectancy of 3.2 years. Of those who survived an additional 2 years, the condition of about one third improved. A substantial majority of those who either showed improvement or died had done so by that age. CONCLUSION: By age 5 years, the prognoses for survival and improvement have to a large extent been clarified. For children who survive to age 5 years, even those in the lowest functioning cohort have a 60% chance of surviving an additional 5 years. Detailing the probabilities of various outcomes at various ages should be useful to parents, pediatricians, and others concerned with children with developmental disabilities.
Age Distribution↗
Simultaneous bilateral pallidoansotomy for idiopathic dystonia musculorum deformans.
A 17-year-old Russian male with a 9-year diagnosed history of dystonia musculorum deformans manifested as severe tortipelvis, lordosis, and axial and appendicular spastic dystonia, refractory to medical therapy, is reported. This patient underwent a simultaneous bilateral pallidoansotomy with dramatic results. Postoperative evaluation revealed sustained alleviation of all dystonic symptoms and abnormal movements. Rapid recovery of useful strength in all limbs as well as dramatic improvement in coordination occurred. Bilateral posteroventral pallidotomy and pallidoansotomy in the past have proven effective in alleviation of all parkinsonian symptoms, including dyskinesia and dystonia, without the concurrent risk of intransigent side effects associated with bilateral thalamotomy or other stereotactic surgical procedures. Pallidoansotomy may prove to be the treatment of choice for idiopathic torsion dystonia and merits further investigation.
Adolescent↗
Proton magnetic resonance spectroscopy in the evaluation of children with congenital heart disease and acute central nervous system injury.
We studied nine infants and children, aged 1 week to 42 months, with severe acute central nervous system injuries associated with cardiac disease or corrective operations by means of single-voxel proton magnetic resonance spectroscopy to determine whether this technique would be useful in predicting neurologic outcome. Proton magnetic resonance spectroscopic data were acquired from the occipital gray and parietal white matter (8 cm3 volume, stimulated echo-acquisition mode sequence with echo time of 20 msec and repetition time of 3.0 seconds) a median of 9 days after operation (range 3 to 42 days). Data were expressed as ratios of areas under metabolite peaks, including N-acetyl compounds, choline-containing compounds, creatine and phosphocreatine, and lactate. Four patients had cerebral insults before operation, one had both a preoperative and a perioperative insult, three had perioperative insults, and one had a prolonged cardiac arrest 2 days after operation. Outcomes (Glasgow Outcome Scale scores) were assigned at discharge and 6 to 12 months after injury. Six patients were in a vegetative state or had severe impairment at discharge, and two still had severe impairment at 6- to 12-month follow-up. Proton magnetic resonance spectroscopy showed lactate in these two patients, along with markedly reduced ratios of N-acetyl compounds to creatine compounds. The other four patients with severe impairment recovered to a level of mild disability at follow-up. Proton magnetic resonance spectroscopy showed no lactate in these four patients; however, one patient showed moderately reduced ratio of N-acetyl compounds to creatine compounds. The three patients who had mild or moderate impairment at discharge showed no lactate and mild or no changes in metabolite ratios; follow-up revealed normal or mild outcomes. Overall, we found that the presence of lactate and markedly reduced ratios of N-acetyl compounds to creatine compounds were predictive of severe outcomes at discharge and long-term follow-up, whereas no lactate and mild or no changes in ratios suggested potential for recovery with at least a mild disability. Continuing investigations are in progress to determine the optimal selection of candidates and timing of proton magnetic resonance spectroscopic studies.
Aspartic Acid↗